RESEARCH

ARTICLE

Droxidopa for the Short-Term Treatment of Symptomatic Neurogenic

Orthostatic Hypotension in Parkinsons Disease (nOH306B)
Robert A. Hauser, MD, MBA,1* Stuart Isaacson, MD,2 Jerome P. Lisk, MD,3 L. Arthur Hewitt, PhD,4 and Gerry Rowse, PhD4
1
University of South Florida, Tampa, Florida, USA
Parkinsons Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA
3
Southern California Movement Disorder Specialists, Inc., Pasadena, California, USA
4
Lundbeck NA Ltd., Deerfield, Illinois, USA

ABSTRACT:

Neurogenic orthostatic hypotension

(nOH) results from failure of norepinephrine responses to
postural change to maintain standing systolic blood pressure (s-SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinsons
disease (PD) and symptomatic nOH. Subjects underwent
up to 2 weeks of double-blind titration of droxidopa or
placebo, followed by 8 weeks of double-blind maintenance treatment (100-600 mg thrice-daily). For the initial
51 subjects (study nOH306A, previously reported), the
primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate
significant change versus placebo at maintenance week
8. For the subsequent 171 subjects (study nOH306B,
reported here), the primary efficacy measure was change
versus placebo on item 1 (dizziness, lightheadedness,
feeling faint, or feeling like you might black out) of the
Orthostatic Hypotension Symptom Assessment (OHSA)
subsection of the OHQ at maintenance week 1. At week
1, mean (standard deviation) improvement on OHSA item

1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P 5 0.018). In addition, mean increase in s-SBP at
week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18)
mmHg for placebo (nominal P value: 0.032). Differences
in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse-event (AE) incidence was similar across
groups, but 12.4% of droxidopa and 6.1% of placebo
subjects withdrew because of AEs. The most common
AEs on droxidopa (vs. placebo) were headache (13.5%
vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study
nOH306B demonstrated subjective (OHSA item 1) and
objective (s-SBP) evidence of short-term droxidopa effiC 2014
cacy (vs. placebo) for symptomatic nOH in PD. V
The Authors. Movement Disorders published by Wiley
Periodicals, Inc. on behalf of International Parkinson and
Movement Disorder Society.

K e y W o r d s : hypotension; orthostatic; Parkinsons

disease; droxidopa; falls; treatment; lightheadedness

-----------------------------------------------------------------------------------------------------------------------------This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.

*Correspondence to: Dr. Robert A. Hauser, University of South Florida, Parkinsons Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, 4001 East Fletcher Avenue, 6th Floor, Tampa, FL 33613, USA; rhauser@health.usf.edu
Funding agencies: Data were derived from clinical trials funded by Chelsea Therapeutics, Inc., which was acquired in 2014 by Lundbeck LLC and is
now renamed Lundbeck NA Ltd.
Relevant conflicts of interest/financial disclosures: R.A.H. is supported in part by a National Parkinson Foundation Center of Excellence Grant. R.A.H. has
received honoraria or payments for consulting, advisory services, and speaking services in the past 12 months from Chelsea Therapeutics, Inc. (now called Lundbeck NA Ltd.). R.A.H.s institution has received research support in the past 12 months from Chelsea Therapeutics, Inc. S.I. has received honoraria for CME,
consultant, research grants, and/or promotional speaker services on behalf of Chelsea Therapeutics, Inc. J.P.L. has no relevant conflicts to report. L.A.H. and
G.R. are employees of Lundbeck LLC.
Full financial disclosures and author roles may be found in the online version of this article.
Received: 30 May 2014; Revised: 19 September 2014; Accepted: 7 October 2014
Published online 9 December 2014 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26086

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Neurogenic orthostatic hypotension (nOH) results

from failure of the autonomic nervous system to generate adequate norepinephrine responses to changes in
posture.1-3 This failure leads to decreases in standing
systolic blood pressure (s-SBP) and often to supine
hypertension. If the s-SBP decreases cannot adequately
maintain cerebral perfusion, nOH can become symptomatic and can vary through the day. Symptoms can
include dizziness, lightheadedness, syncope, visual disturbances, neck/shoulder pain, difficulty in concentrating, and nonspecific complaints, such as weakness or
fatigue.1 nOH is common in Parkinsons disease (PD):
In a single-center review of 1,125 PD patients, the
prevalence of symptomatic nOH was 18%,4 and in
studies defining nOH solely by s-SBP change, the
reported prevalence was as high as 47% in community-based5 and 58% in hospital-based6 PD populations. In PD, nOH may contribute to falls,7,8 which
have been reported to occur in 81% of PD patients
within 15 years after PD diagnosis.9 Such falls may
necessitate hospitalization10 and can lead to significant
morbidity.8,9
Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an
oral prodrug converted to norepinephrine by dopa
decarboxylase both centrally and peripherally.11 In
early, small clinical studies of patients with symptomatic nOH in MSA and pure autonomic failure, the
agent provided hemodynamic12-14 and symptomatic13
benefit. More recently, droxidopa has been evaluated
in several large, multicenter clinical trials (studies
nOH301, nOH302, and nOH306). Studies nOH30115
(n 5 162) and nOH30216 (n 5 101) included patients
with symptomatic nOH in PD, MSA, pure autonomic
failure, and nondiabetic autonomic neuropathy. In
study nOH301, responders to open-label droxidopa
titration underwent a 7-day washout and then were
randomized in a 7-day double-blind trial of droxidopa
versus placebo. Significant improvement versus placebo was demonstrated by measures including composite score (primary endpoint) on the Orthostatic
Hypotension Questionnaire (OHQ), a validated nOHspecific severity scale,17 scores on individual OHQ
items, such as dizziness/lightheadedness, and mean sSBP. In study nOH302, responders to open-label droxidopa titration received additional open-label treatment for 7 days and then were randomized to
droxidopa or placebo for 14 days. In this trial,
changes in dizziness/lightheadedness score (primary
outcome) and mean s-SBP were not significantly different between droxidopa- and placebo-treated subjects.
However, change in OHQ composite score significantly favored droxidopa. In addition, an integrated
analysis of studies nOH301 and nOH302 demonstrated a significant increase in mean s-SBP (without a
marked increase in supine hypertension), accompanied
by significant improvement on OHQ items for dizziness/lightheadedness, weakness, fatigue, and nOH

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impact on activities requiring standing a short or long

time and walking a short or long time.18
Study nOH306 differed from these other trials in
that it enrolled only patients with symptomatic nOH
resulting from PD and was designed as an intentionto-treat study, rather than only including initial responders. In addition, it was originally designed to
evaluate the clinical efficacy of droxidopa over an 8week double-blind period. In a preplanned interim
efficacy analysis, the initial 51 subjects (study
nOH306A) did not demonstrate a significant difference across groups in the trials primary efficacy measure, change in OHQ composite score.19 However,
exploratory analyses19 suggested potential efficacy for
dizziness/lightheadedness score and for falls and led to
further hypotheses and a corresponding change in the
trials primary efficacy measure while data for subsequent subjects remained blinded. The resulting
analyses of the subsequent 171 enrolled patients
(Study nOH306B) are presented here.

Patients and Methods

Study Subjects
For all study nOH306 subjects, key inclusion criteria
included a clinical diagnosis of PD and age 18 years.
In addition, subjects were required to have signs and
symptoms of nOH, including a blood pressure (BP)
decrease 20 mmHg systolic or 10 mmHg diastolic
upon standing for up to 3 minutes,2 an OHQ composite
score 3, and a study-investigator nOH rating of 3 (at
least mild) on the clinician-reported Clinical Global
Impression-Severity (cCGI-S) scale. Key exclusion criteria included use of vasoconstricting agents or longacting antihypertensive medications; sustained, severe
hypertension (180/110 mmHg while seated or supine);
and a MiniMental State Examination score 23.
Patients with significant uncontrolled cardiac arrhythmia, unstable angina, congestive heart failure, or a history of myocardial infarction were also excluded.

Study Design
Study nOH306 was a phase III, multicenter, randomized, placebo-controlled, double-blind, parallel-group
trial (ClinicalTrials.gov identifier: NCT01176240). Subjects were randomized (1:1 ratio) to double-blind droxidopa or placebo titration (up to 2 weeks), followed by
8 weeks of double-blind maintenance at each subjects
optimized dosage (100-600 mg thrice-daily [TID]).
During titration, study drug was increased from
100 mg TID in 100-mg TID increments until the subject either (1) became asymptomatic for nOH (cCGI-S
score of 1), or nearly asymptomatic (cCGI-S score of
2), (2) had a systolic BP (SBP) 180 mmHg or diastolic
BP (DBP) 110 mmHg after 10 minutes supine, on
three consecutive measurements during 1 hour, (3)

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experienced intolerable adverse events (AEs), or (4)

reached the maximum dosage of 600 mg TID. Subjects
meeting criteria 2 or 3 at a dosage >100 mg TID were
eligible to continue at their previous lower dosage.
During the maintenance period, a single 100-mg TID
study-drug reduction was permitted for subjects with
AEs considered to be related to study drug. Throughout the study, all PD medications were to be held stable. Midodrine was disallowed, but fludrocortisone
could be continued at a dosage that had been stable for
2 weeks before start of study drug. Bedtime use of a
short-acting antihypertensive was also permitted.

Study Assessments
The OHQ, cCGI-S ratings, and patient-reported
Clinical Global Impression-Severity (pCGI-S) ratings
were completed at baseline (i.e., at randomization
for study-drug titration) and at maintenance weeks
1, 2, 4, and 8 (hereafter simply called weeks).
Clinician- and patient-reported Clinical Global
Impression-Improvement (cCGI-I and pCGI-I) ratings
were obtained at weeks 1, 2, 4, and 8. The International Parkinson and Movement Disorder Society
(MDS) UPDRS (MDS-UPDRS)20 and the 39-item Parkinsons Disease Questionnaire (PDQ-39)21 were completed at baseline and week 8. An orthostatic standing
test was conducted at time points including baseline
and weeks 1, 2, 4, and 8. In each test, supine BP and
heart-rate measurements (head and torso elevated 30
degrees from horizontal) were obtained at 210
minutes, 25 minutes, and immediately before standing, followed by values upon standing (minute 0) and
after 3 minutes of standing.
Study assessments were conducted 3 hours after the
subjects first daily study-drug dose (during an ON
state, if the subject was having motor fluctuations).
Additionally, subjects were instructed to record, in a
daily electronic diary, all of their falls, defined as
unexpectedly coming to rest on the ground, floor, or a
lower level from where the patient starteda phrasing
consistent with standard characterizations.22 Fall-related
injuries were defined as prespecified AEs (e.g., contusions) on the day of or the day after a reported fall.

Efficacy Measures
The OHQ consists of the six-item Orthostatic
Hypotension Symptom Assessment (OHSA), assessing
dizziness/lightheadedness (OHSA item 1), vision disturbance, weakness, fatigue, trouble concentrating,
and head/neck discomfort, and the four-item Orthostatic Hypotension Daily Activity Scale (OHDAS),
assessing nOH interference with daily activities requiring standing a short time, standing a long time, walking a short time, and walking a long time.17 Each item
is scored from 0 (not bothered/no interference) to 10
(worst possible/complete interference), describing the

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preceding week. The responses yield a composite

OHSA score and a composite OHDAS score (each is
the average of the item scores not rated 0 at baseline)
and also an overall composite score (the average of
the OHSA and OHDAS composite scores).
The original primary outcome measure in study
nOH306 had been OHQ composite score at 8 weeks.
A subsequent change in primary outcome measure
emerged from an interplay between regulatory requirements and the outcomes of other droxidopa trials.
Study nOH306 was undertaken shortly after study
nOH302, a 2-week double-blind trial with a
randomized-withdrawal design, had failed to demonstrate significant efficacy by its primary outcome measure, OHSA item 1 score, perhaps owing to an
unanticipated carryover of droxidopa effect among subjects switched to placebo.16 However, OHQ composite
score, assessed post hoc, did identify efficacy. Accordingly, study nOH306 was designed as an
8-week double-blind trial with OHQ composite score
change as its primary endpoint. Because PD patients
had been only a subgroup in study nOH302, but would
compose all the subjects in study nOH306, study
nOH306 included a preplanned interim analysis of the
primary outcome, which ultimately predicted futility, as
described above. Meanwhile, the U.S. Food and Drug
Administration (FDA) had consented to use study
nOH301, a 1-week double-blind trial of droxidopa
inception, in a new drug application (NDA). Hence, the
remainder of study nOH306 could be repurposed, as
study nOH306B, to examine fall rates. In March 2012,
the NDA was rejected, and the FDA advised that resubmission would require a study corroborating the efficacy noted in study nOH301. By protocol amendment,
and without data unblinding, the study nOH306B primary outcome was changed to OHSA item 1 score
change at 1 week, thereby aligning it with the duration
of study nOH301 while focusing the evaluation of subjective efficacy on a patient self-rating of the primary
symptoms of nOH. OHSA item 1 asks respondents to
rate their dizziness, lightheadedness, feeling faint, or
feeling like you might black out.17
In study nOH306B, secondary efficacy variables (in
hierarchical order) included mean change on OHSA
item 1 from baseline to week 2; mean change on
OHSA item 1 from baseline to week 4; mean change
in lowest s-SBP between 0 and 13 minutes of standing, from baseline to week 1; mean change on OHSA
item 1 from baseline to week 8; aggregated patientreported falls from baseline to week 8, expressed as
falls per patient-week; and mean change in OHQ
composite score from baseline to week 8.

Safety Data
Treatment-emergent AEs (TEAEs), vital signs, clinical laboratory values, and electrocardiographic

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findings were collected as safety parameters. Safety

assessments also included change in PD, as measured
by MDS-UPDRS and PDQ-39 scores.

Statistical Analyses
The primary efficacy analysis was based on the full
analysis set (FAS), comprising all randomized subjects
who received at least one dose of study drug and provided week 1 OHSA item 1 data. Treatment-group
differences were tested using an analysis of covariance
(ANCOVA) model with effects for baseline and treatment. Where the assumptions of an ANCOVA were
not met, a rank ANCOVA was used, based on
Cochran-Mantel-Haenszels test. Statistical significance
was set at the two-sided, 5% level. Secondary efficacy
endpoints were analyzed using a similar ANCOVA,
except for falls, which were assessed by Wilcoxons
rank-sum tests. A hierarchical testing strategy was
used to control the family-wise error rate at the 5%
level. For responder analyses of the primary efficacy
endpoint, Fishers exact test was used.

Sample-Size Calculation
The sample size for study nOH306B was based on
the study nOH306A finding of a 1.5-unit difference
between droxidopa and placebo in improvement of
dizziness/lightheadedness (OHSA item 1) at 1 week,
with a 3.3-unit standard deviation (SD). Consequently,
a two-sided test with P  0.05 would require 154
patients for an 80% power to detect a difference
between groups.

Study Oversight
The study was conducted in full conformance with
International Conference on Harmonization guidelines
for good clinical practice. The study protocol was
approved by an institutional review board for each
study site. Before study procedures, all subjects provided written informed consent. Data were collected
by investigators and study-site staff and were analyzed
by the study sponsor, Lundbeck NA Ltd.

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placebo, but erroneously received droxidopa (for 3

days and for an estimated 12 days) resulting from
study-site error in dispensing study drug. They are
included in the safety sets droxidopa group and the
FASs placebo group. There were no meaningful differences in baseline characteristics between FAS subjects
randomized to droxidopa and those randomized to placebo (Table 1). Carbidopa/levodopa was the most common concomitant PD medication, taken by 70 subjects
(78.7%) in the safety sets droxidopa group and 65
(79.3%) in the safety sets placebo group. A larger proportion of subjects took fludrocortisone in the droxidopa group (30 safety-set subjects; 33.7%) than in the
placebo group (16 safety-set subjects; 19.5%).

Study-Drug Optimization
In the FAS, the most common reason for stopping
dosage titration was that the subject reached the maximum dose allowed, which occurred in 28 subjects
(40.6%) in the droxidopa group and 42 (53.8%) in the
placebo group. Additional reasons for stopping dosage
titration were that the subject became asymptomatic
(29 [42.0%] vs. 26 [33.3%]), experienced sustained
SBP >180 mmHg or DBP >110 mmHg (4 [5.8%] vs.
12 [15.4%]), or experienced intolerable AEs (8 [11.6%]
vs. 2 [2.6%]). The mean (SD) daily study-drug dosage
after dose optimization was 436 (163) mg in the droxidopa group and 468 (165) mg in the placebo group.

Primary Efficacy Analysis

From baseline to week 1, mean (SD) improvement in
OHSA item 1 score was 2.3 (2.95) units in the droxidopa group versus 1.3 (3.16) in the placebo group, significantly favoring droxidopa (difference, 21.0; 95%
confidence interval: 22.0, 0.0; P 5 0.018; Fig. 2, top).

Responder Analyses of the Primary Endpoint

Compared with placebo subjects, significantly
greater proportions of droxidopa subjects met a variety of primary endpoint responder criteria, including
improvement 2 units, 3 units, 4 units, 25%,
and 50% (Supporting Fig. A).

Results
Secondary Efficacy Analyses
Eighty sites, all in the United States, participated in
the trial. Data collection began in June 2010 and
ended in October 2012.

Study Subjects
Of the 225 patients who entered study nOH306, 174
were randomized in study nOH306B (Fig. 1). Three of
them did not receive study drug; hence, the safety set
comprised 171 subjects, of whom 147 (86.0%) provided an OHSA item 1 self-rating at week 1, thereby
composing the FAS. Two subjects were randomized to

Changes in OHSA item 1 score from baseline to

weeks 2, 4, and 8 favored droxidopa, although they
were not statistically significant (Fig. 2, top; Table 2).
The mean (SD) change in lowest s-SBP from baseline to
week 1 was 16.4 (18.85) mmHg in the droxidopa
group, compared with 10.7 (20.18) in the placebo
group (nominal P value: 0.032). Aggregate rate of falls
per patient-week was 0.39, compared with 1.09 (nominal P value: 0.853). Mean (SD) change in OHQ composite score from baseline to week 8 was 22.2 (2.29),
compared with 22.0 (2.18; nominal P value: 0.286).

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FIG. 1. Subject disposition. *Includes 1 subject randomized to placebo who erroneously received droxidopa. DB, double-blind.

Exploratory BP Analyses

Exploratory CGI Analyses

Mean changes from baseline in lowest s-SBP (Supporting Table A) favored the droxidopa group at
week 2 by 6.1 mmHg (nominal P value: 0.087) and at
week 8 by 4.1 mmHg (nominal P value, 0.160). The
mean changes from baseline to week 4 slightly favored
the placebo group, by 0.2 mmHg (nominal P value:
0.799).

Changes in cCGI-S scores favored droxidopa over

placebo (see Supporting Table A), with nominal P values <0.05 at weeks 1 and 2. pCGI-S scores showed
no notable differences between treatment groups. Similarly, cCGI-I scores favored droxidopa at weeks 1, 2,
and 8, but pCGI-I scores showed no notable
differences.

Exploratory Falls Analyses

The droxidopa group had 229 reported falls,
whereas the placebo group had 716 (nominal P value:
0.677). The difference in number of falls was evident
as early as the end of titration, by which time there
had been 46 reported falls in the droxidopa group and
232 in the placebo group.

Exploratory OHQ Analyses

In general, changes from baseline in OHQ composite score, OHSA composite score, and OHDAS composite score favored the droxidopa group (see
Supporting Table A).

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Safety
Overall, 82.0% of the droxidopa group and 79.3%
of the placebo group reported TEAEs (Table 3). In the
droxidopa group, the incidence of headache, dizziness,
nausea, and hypertension was higher than in the placebo group. For hypertension, it was 7.9%, compared
with 1.2% for placebo. However, for the combined
terms hypertension, blood pressure increased,
and blood pressure systolic increased, it was
12.4%, compared with 8.5%. In both groups, most
TEAEs were mild or moderate in severity.
TEAEs leading to discontinuation occurred in 11
subjects (12.4%) in the droxidopa group and 5

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TABLE 1. Subjects Baseline Characteristics

Variable

Demographic characteristics (FAS)

N
Age at screening, years
Mean (SD)
Range
Sex, n (% of group)
Male
Female
Race, n (% of group)
White
Other
Weight, kg
Mean (SD)
Range
nOH characteristics (FAS)
N
OHSA item 1 score
Mean (SD)
Range
OHQ composite score
Mean (SD)
Range
OHSA composite score
Mean (SD)
Range
OHDAS composite score
Mean (SD)
Range
cCGI-S rating
Mean (SD)
Range
pCGI-S rating
Mean (SD)
Range
Lowest s-SBPa
Mean (SD)
Range
PD characteristics (safety set)
N
H & Y stage, n (% of group)
0
1
2
3
4
5
Not recorded

Droxidopa Group

Placebo Group

69

78

72.5 (8.0)
41.4-91.7

71.9 (7.7)
53.5-86.3

45 (65.2)
24 (34.8)

52 (66.7)
26 (33.3)

65 (94.2)
4 (5.8)

75 (96.2)
3 (3.8)

78.1 (17.4)
48.6-122.0

78.2 (15.5)
52.7-122.3

69

78

5.1 (2.04)
0-9

5.1 (2.33)
0-10

5.5 (1.54)
3-9

5.7 (1.64)
3-9

5.1 (1.66)
2-9

5.3 (1.58)
2-9

5.8 (1.97)
2-10

6.2 (2.14)
1-10

4.4 (0.95)
3-6

4.6 (0.94)
3-7

4.3 (1.27)
1-7

4.4 (1.26)
2-7

94.7 (21.53)
52-145

95.7 (20.09)
44-144

89b

82

8
2
42
29
5
2
1

(9.0)
(2.2)
(47.2)
(32.6)
(5.6)
(2.2)
(1.1)

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The proportion of subjects with a reported fallrelated injury was higher in the placebo group than in
the droxidopa group, at 25.6% compared with 16.9%
(no statistical analysis). The incidence of contusion,
excoriation, and skin laceration was also higher (see
Table 3). Injuries in the placebo group included 2 subjects with fractures and 1 with traumatic brain injury.
There were no similar injuries in the droxidopa group.
Overall, vital signs, clinical laboratory values, and
electrocardiographic findings showed no clinically significant trends or differences between treatment groups.
At orthostatic standing tests, a total of 7 droxidopa
recipients (7.9% of 89) and 4 placebo recipients (4.9%
of 82) exhibited supine hypertension, defined as an SBP
>180 mmHg at all 3 assessments during a 10-minute
supine period (see Table 3). No subject in either group
had a recorded supine SBP >180 mmHg after week 2.
Among PD parameters (Supporting Table B), MDSUPDRS scores showed similar mean decreases
(improvements) across treatment groups, and PDQ-39
scores showed mean decreases (improvements) on
almost all scales and in the index score.

15
4
24
26
11

(18.3)
(4.9)
(29.3)
(31.7)
(13.4)
0
2 (2.4)

During an orthostatic standing test, between 0 and 13 minutes standing.

Includes 2 subjects randomized to placebo who erroneously received
droxidopa.
b

(6.1%) in the placebo group. In the droxidopa group,

2 such AEs were severe (BP increased and hypertension), 6 were moderate (atrial fibrillation, BP
increased, hallucination, hypotension, mental status
changes, and PD), and 3 were mild (2 cases of hypertension and 1 of abnormal dreams). In the placebo
group, 1 such AE was severe (hypertension). The
remaining 4 were moderate (BP increased, gastroenteritis, malaise, and syncope). No subjects died during
the study.

FIG. 2. OHSA item 1 changes from baseline in study nOH306B and

study nOH306 overall (observed cases). *P < 0.05 versus placebo,
ANCOVA; **P < 0.01 versus placebo, ANCOVA. BL, baseline; SE,
standard error.

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TABLE 2. Efficacy analyses: primary and secondary

endpointsa

Endpoint

Droxidopa
Group

Primary
OHSA item 1 score,
baseline to week 1
N
69
Mean (SD) change
22.3 (2.95)
Secondary, assessed hierarchically
OHSA item 1 score,
baseline to week 2
N
68
Mean (SD) change
21.9 (2.86)
OHSA item 1 score,
baseline to week 4
N
67
Mean (SD) change
22.0 (3.08)
Lowest standing systolic
BP,c mmHg,
baseline to week 1
68
N
16.4 (18.85)
Mean (SD) change
OHSA item 1 score,
baseline to week 8
N
63
Mean (SD) change
22.1 (3.03)
Fallsd
N
69
Mean falls per
0.39
patient-week
OHQ composite score,
baseline to week 8
N
63
Mean (SD) change
22.2 (2.29)

Placebo
Group

P Value or
Nominal
P Valueb
(ANCOVA)

78
21.3 (3.16)

0.018

75
21.6 (2.97)

0.600

TABLE 3. Safety findings (safety set)

73
21.5 (2.74)

0.308

78
10.7 (20.18)

0.032b

68
21.5 (2.91)

0.187b

78
1.09

0.853b,e

68
22.0 (2.18)

0.286b

Variable

FAS, missing data excluded.

P values after OHSA item 1 score change from baseline to week 2 are
nominal values unadjusted for nonsignificant outcomes in the preceding
hierarchical analyses.
c
During an orthostatic standing test, between 0 and 13 minutes standing.
d
Subject-reported (by electronic diary) throughout the study and aggregated across all subjects in each treatment group.
e
Wilcoxons rank-sum test.
b

Discussion
OH is a potentially incapacitating disorder associated with significant morbidity, including falls and
hospitalization.23 In the present study of symptomatic
nOH in PD, droxidopa improved cardinal nOH symptoms of dizziness/lightheadedness, as demonstrated by
the primary outcome measure, change in OHSA item
1 score (compared with placebo) from baseline to
week 1. This subjective outcome was supported by
objective improvement in s-SBP from baseline to week
1. Thus, study 306B provides evidence for the shortterm efficacy of droxidopa to treat nOH in PD.
In study nOH306B, changes from baseline in OHSA
item 1 score and s-SBP favored droxidopa at weeks 2
through 8, but the differences from placebo were not

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Movement Disorders, Vol. 30, No. 5, 2015

statistically significant. Exactly why sustained benefit

was not observed is a matter of speculation. It is possible that a pretreatment adrenoreceptor hypersensitivity
diminished after the introduction of norepinephrine
replacement therapy.14,24 If so, further dose titration
may be required to maintain clinical benefit. Subjects
may also have exhibited response shift in their patientreported outcomes, in which a continuing experience of
improvement recalibrates patients recollections of their
baseline symptoms.25,26 In addition, the study did not
control for subjects usage of nonpharmacological strategies addressing nOH, such as increased hydration.
However, we also note that the lack of a significant difference across groups at week 8 may have been a result

Droxidopa Group
(N 5 89a)

TEAEs, n (% of group)
Any TEAEs
73 (82.0)
Any severe TEAEs
8 (9.0)
Any serious TEAEs
5 (5.6)
Any TEAEs leading to
11 (12.4)
discontinuation
Deaths
0
TEAE types,b n (% of group)
Headache
12 (13.5)
Dizziness
9 (10.1)
Fatigue
7 (7.9)
Nausea
7 (7.9)
Hypertension
7 (7.9)
Excoriation
5 (5.6)
Edema peripheral
5 (5.6)
Contusion
4 (4.5)
Diarrhea
4 (4.5)
PD
4 (4.5)
Gait disturbance
4 (4.5)
Skin laceration
3 (3.4)
BP increased
3 (3.4)
Urinary tract infection
3 (3.4)
Insomnia
3 (3.4)
Dehydration
3 (3.4)
Dyspepsia
3 (3.4)
Hematuria
3 (3.4)
Back pain
2 (2.2)
Paresthesia
2 (2.2)
Nasopharyngitis
1 (1.1)
Supine hypertension,c,d n/N (% of group)
At baseline
0/89
During study drug
2/87 (2.3)
optimization
Week 1
4/82 (4.9)
Week 2
1/70 (1.4)
Week 4
0/67
Week 8
0/65
Overall
7/89 (7.9)

Placebo Group
(N 5 82)

65 (79.3)
9 (11.0)
4 (4.9)
5 (6.1)
0
6
4
5
2
1
7
4
10
4
2
7
5
3
2
1
1
5
3
4

(7.3)
(4.9)
(6.1)
(2.4)
(1.2)
(8.5)
(4.9)
(12.2)
(4.9)
(2.4)
0
(8.5)
(6.1)
(3.7)
(2.4)
(1.2)
(1.2)
0
(6.1)
(3.7)
(4.9)

2/82 (2.4)
1/82 (1.2)
2/80 (2.5)
0/75
0/72
0/69
4/82 (4.9)

a
Includes 2 subjects randomized to placebo who erroneously received
droxidopa.
b
The types listed (by Medical Dictionary for Regulatory Activities preferred
term) are all those reported in 3.0% of subjects in either treatment group.
c
SBP >180 mmHg at all three supine assessments over a 10-minute period
(before standing) during an orthostatic standing test.
d
Observed cases.

D R O X I D O P A

of inadequate power. When results from studies

nOH306A and nOH306B are combined (Fig. 2, bottom), the difference across groups in change on OHSA
item 1 from baseline to week 8 approached statistical
significance (P 5 0.077 vs. placebo).
Among potential efficacy signals during study
nOH306, droxidopa appears to have had an impact
on patient-reported falls. In the present study
(nOH306B), the droxidopa group had 68% fewer
patient-reported falls than the placebo group (229 vs.
716). Among the first 51 PD patients to enter this
studys protocol (nOH306A), the difference was 59%
(79 vs. 192). In both comparisons, falls were nonnormally distributed among subjects and hence were
difficult to model. In a post-hoc analysis of the
nOH306B falls data, use of the Poisson inverse Gaussian distribution27 showed a statistically significant
difference
between
droxidopa
and
placebo
(P 5 0.018). Signals of potential droxidopa benefit in
this study also included an impact on fall-related
injuries.
Overall, droxidopa was safe and reasonably well
tolerated. The incidence of AEs was similar in both
groups, but 11 subjects (12.4%) in the droxidopa
group and 5 in the placebo group (6.1%) withdrew
because of AEs. The most common AEs associated
with droxidopa were headache, dizziness, fatigue, nausea, and hypertension. In patients with nOH, supine
hypertension is a particular safety concern.28 In this
study, the rates of supine hypertension were relatively
low. However, the study excluded patients with an
observed BP 180/110 mmHg while seated or supine
at screening.
As described above, previous droxidopa studies have
shown short-term benefit for signs and symptoms of
nOH across a variety of underlying neurological disorders involving autonomic dysfunction.15,16,18 The present study provides evidence for short-term benefit in
patients with PD. It is important to recognize that trials to date have only demonstrated efficacy over 1 or
2 weeks. Whether droxidopa is effective beyond this
time frame is unclear. In February 2014, droxidopa
received U.S. approval with an indication for the treatment of symptomatic nOH caused by primary autonomic failure (PD, MSA, and pure autonomic failure),
dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy. The prescribing information states that effectiveness beyond 2 weeks of
treatment has not been demonstrated and that
continued effectiveness. . . should be assessed periodically.29 We anticipate that in clinical practice, treating physicians will want to assess both initial and
continuing symptomatic benefit. If no benefit is
obtained with initial titration to the highest recommended or well-tolerated dose, the medication should
be discontinued. If initial benefit is achieved, but
symptoms of nOH re-emerge or worsen, one might

F O R

O H

I N

P D

consider increasing the dose (while not exceeding the

recommended range) to see if symptoms can be ameliorated. If benefit for nOH appears to have been lost,
one can withdraw the medication to assess continued
efficacy. A planned phase IV trial of the durability
of droxidopa efficacy will have a design in which
the dose can be adjusted over time as clinically
appropriate.
Acknowledgments: Editorial assistance in the form of substantive
editing, copyediting, styling, and figure preparation was provided by
Michael Feirtag of The Curry Rockefeller Group, LLC, and funded by
Lundbeck LLC.

References
1.

Freeman R. Clinical practice. Neurogenic orthostatic hypotension.

N Engl J Med 2008;358:615-624.

2.

Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on

the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res
2011;21:69-72.

3.

Isaacson SH, Skettini J. Neurogenic orthostatic hypotension in Parkinsons disease: evaluation, management, and emerging role of
droxidopa. Vasc Health Risk Manag 2014;10:1-8.

4.

Ha AD, Brown CH, York MK, Jankovic J. The prevalence of

symptomatic orthostatic hypotension in patients with Parkinsons
disease and atypical parkinsonism. Parkinsonism Relat Disord
2011;17:625-628.

5.

Allcock LM, Ullyart K, Kenny RA, Burn DJ. Frequency of orthostatic hypotension in a community based cohort of patients with
Parkinsons disease. J Neurol Neurosurg Psychiatry 2004;75:14701471.

6.

Senard JM, Ra S, Lapeyre-Mestre M, et al. Prevalence of orthostatic hypotension in Parkinsons disease. J Neurol Neurosurg Psychiatry 1997;63:584-589.

7.

Gray P, Hildebrand K. Fall risk factors in Parkinsons disease.

J Neurosci Nurs 2000;32:222-228.

8.

Michalowska M, Fiszer U, Krygowska-Wajs A, Owczarek K. Falls

in Parkinsons disease. Causes and impact on patients quality of
life. Funct Neurol 2005;20:163-168.

9.

Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multicenter

Study of Parkinsons disease: non-L-dopa-responsive problems
dominate at 15 years. Mov Disord 2005;20:190-199.

10.

Koller WC, Glatt S, Vetere-Overfield B, Hassanein R. Falls and

Parkinsons disease. Clin Neuropharmacol 1989;12:98-105.

11.

Biaggioni I, Robertson D. Endogenous restoration of noradrenaline

by precursor therapy in dopamine-beta-hydroxylase deficiency.
Lancet 1987;2:1170-1172.

12.

Freeman R, Landsberg L, Young J. The treatment of neurogenic

orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine:
a randomized, placebo-controlled, crossover trial. Neurology 1999;
53:2151-2157.

13.

Mathias CJ, Senard JM, Braune S, et al. L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, doseranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001;11:235-242.

14.

Kaufmann H, Saadia D, Voustianiouk A, et al. Norepinephrine

precursor therapy in neurogenic orthostatic hypotension. Circulation 2003;108:724-728.

15.

Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled,
phase 3 trial. Neurology 2014;83:328-335.

16.

Biaggioni I, Freeman R, Mathias CJ, Low P, Hewitt LA,

Kaufmann H. Randomized-withdrawal study of patients with
symptomatic neurogenic orthostatic hypotension responsive to
droxidopa. Hypertension 2014 Oct 27. pii: HYPERTENSIONAHA.114.04035. [Epub ahead of print].

17.

Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K,

Freeman R. The Orthostatic Hypotension Questionnaire (OHQ):

Movement Disorders, Vol. 30, No. 5, 2015

653

H A U S E R

18.

E T

A L

validation of a novel symptom assessment scale. Clin Auton Res

2012;22:79-90.

24.

Esler M. An explanation of the unexpected efficacy of L-DOPS in

pure autonomic failure. Clin Auton Res 2004;14:356-357.

Mathias CJ, Low PA, Freeman R, Hewitt LA, Kaufmann H. Integrated efficacy analysis of droxidopa in 2 double-blind, placebocontrolled, phase 3 studies in patients with neurogenic orthostatic
hypotension. Poster presented at the Movement Disorder Societys
16th Annual International Congress of Parkinsons Disease and
Movement Disorders (MDS), 17-21 June 2012, Dublin, Ireland.
Poster 1296.

25.

Ahmed S, Mayo NE, Wood-Dauphinee S, Hanley JA, Cohen SR.

Response shift influenced estimates of change in health-related
quality of life poststroke. J Clin Epidemiol 2004;57:561-570.

26.

Schwartz CE, Finkelstein JA. Understanding inconsistencies in

patient-reported outcomes after spine treatment: response shift
phenomena. Spine J 2009;9:1039-1045.

27.

Canning CG, Sherrington C, Lord SR, et al. Exercise for falls prevention in Parkinsons disease: a randomized controlled trial
[abstract]. Mov Disord 2013;28(Suppl S1):S158.

28.

Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association between supine hypertension and orthostatic hypotension in
autonomic failure. Hypertension 2003;42:136-142.

29.

U.S. Food and Drug Administration. Northera (droxidopa) capsules label. Available at: http://www.accessdata.fda.gov/drugsatfda_
docs/label/2014/203202lbl.pdf. Accessed 26 July 2014.

19.

Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with

neurogenic orthostatic hypotension associated with Parkinsons disease (NOH306A). J Parkinsons Dis 2014;4:57-65.

20.

Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder

Society-sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing
results. Mov Disord 2008;23:2129-2170.

21.

Jenkinson C, Fitzpatrick R, Peto V, Greenhall R, Hyman N. The

Parkinsons Disease Questionnaire (PDQ-39): development and
validation of a Parkinsons disease summary index score. Age Ageing 1997;26:353-357.

22.

Gibson MJ, Andres RO, Isaacs B. A report of the Kellogg international working group on the prevention of falls in the elderly. The prevention of falls in later life. Danish Med Bull 1987;34(Suppl 4):1-23.

23.

Shibao C, Grijalva CG, Raj SR, Biaggioni I, Griffin MR. Orthostatic hypotension-related hospitalizations in the United States. Am
J Med 2007;120:975-980.

654

Movement Disorders, Vol. 30, No. 5, 2015

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